Familial hypercholesterolaemia (FH) is a common inherited condition that causes high levels of cholesterol in the blood and increases an individual’s risk of developing early heart disease.

Since statins effectively lower cholesterol and reduce risk in FH patients, it is important to be able to identify patients early and accurately, and many clinicians now believe that DNA-based tests will be useful for this. So what are the genetic causes of FH? Since we know that FH is a disease where the LDL cholesterol particle is cleared too slowly from the blood, we would guess that it is going to be caused by having something wrong (called a “mutation”) in genes that code for important proteins in this clearance process. As it turns out, this is exactly right.



Mutations in the gene for the LDL receptor
The most common cause of FH in patients in the UK is due to their having a mutation in the gene coding for a receptor protein whose job is to remove the LDL cholesterol particles from the blood. This gene was the first to be identified, by Mike Brown and Joe Goldstein working in Dallas in America, and formed part of the work for which they were awarded the Nobel Prize in 1985. The receptor protein is shaped like a seven fingered hand that comes out of the surface of cells such as in the liver. The LDL particle, which can be imagined to be like a tennis ball, bumps into the receptor and sticks to it. The receptor and particle then sink down into the cell, and the cholesterol is removed from the blood. When the receptor and particle move into the cell they enter a particular area (called the lysosome) where there is a change in the acidity, which causes the shape of the receptor to alter, and the particle and receptor separate (you can think of it like the fingers of the hand releasing the tennis ball). The receptor then recycles back to the surface to look for more LDL, and during its normal life, each receptor protein may do this 100 or 150 times.

The LDL in the cell is then broken down and the cholesterol used or chemically changed. The most important organ in the body for removing cholesterol from the blood is the liver. Liver cells have enzymes which break down the cholesterol into a different chemical form called “bile”. This is stored in the gall bladder and then released into the intestine to help the body’s digestive processes. In this way excess cholesterol can be flushed out of the body.

We now know that there are more than 700 different defects that can occur in the gene for the receptor which prevent it functioning in the correct way. At least 100 different defects have been found in patients in Britain, some only occurring in one family, while others are found in many different families. Interestingly, we share some of these mutations with patients in Norway, and these may have been brought over to England by the Vikings! Whatever the exact mutation is, the end effect is the same, that there are much less than the normal number of receptors present on the surface of the liver cell and so LDL cholesterol is cleared more slowly.

Mutations in the gene for apolipoprotein B
Apolipoprotein B (ApoB for short) is a very large protein that is involved in wrapping around the cholesterol in the LDL particle and keeping it stable. There are a number of different apoproteins that can be found in the blood and their job is to stabilise lipid particles of various different sorts so that they can be moved through the blood. For example, ApoA1 is found on HDL cholesterol (the good cholesterol) whereas ApoB is found on several different particles but mainly on LDL (there are also ApoCs and ApoE which do different jobs). It turns out that there is one small region of ApoB which is important in making sure the LDL can bind effectively to the LDL receptor. You can think of it like the ApoB key fitting into the receptor lock, and that even a rather small change in the shape of the key means it will not fit. We now know that about 5% of FH patients in the UK have got one particular mutation in the gene that makes ApoB which causes this problem. Interestingly, this particular change appears to have occurred only once during human history (probably about 5,000 years ago), and that all the patients with this defect come from this common ancestor. Although, to be strictly correct, this disorder is given a different name (familial defective ApoB or FDB), essentially it looks exactly like LDL receptor FH. These patients may not be quite so severely affected, and seem to respond particularly well to statin treatment.

A new gene causing FH - PCSK9
Two years ago a third gene causing FH was found. We still do not know exactly how this works but the gene, which is called PCSK9, makes an enzyme whose normal job it is to break down some of the receptor protein whilst it is inside the cell and before it recycles. People with FH with a mutation in this gene make an enzyme that works too well, and so it breaks down more of the receptor than it should. The consequence of this is that there are fewer receptors available on the surface of the liver cell and, therefore, cholesterol cannot be cleared as normal. Although 11 different defects have been found in the PCSK gene, only one appears very common in patients in the UK. About 2% of FH patients appear to have this particular mutation and, unfortunately, they are rather severely affected, having much higher than average untreated cholesterol levels, and still having unhealthily high levels when treated with statins. These patients may need treatment with more than one type of drug (such as statin plus ezetimibe) in order to reach target levels.

Other genes for FH?
Even when the research laboratory has looked at the whole of the genes for the receptor, ApoB and PCSK9, there are still some FH patients where no mutation can be found. There are two possible explanations for this. It may well be that these patients actually have not got “true” FH, but rather have high cholesterol because of a number of different genetic causes, as well, perhaps, as having a bad environment (such as diet). The other possibility is that, there is a fourth (or even a fifth) gene that still needs to be found that could be explaining this. Only further research will be able to sort this out.
The cholesterol found in the blood partly comes from what we eat in the diet and partly is made every day in the liver. The cholesterol, together with triglycerides, is “wrapped up” by ApoB and other apoproteins, and is released from the liver as a VLDL particle. The triglycerides are removed in muscle and used as energy or in the fat tissue where it is laid down for future use. The particle that is left becomes LDL.

Useful websites for further information: http://www.londonideas.org/

© Copyright H·E·A·R·T UK Ltd

Top of Page